ABSTRACT/SUMMARY Immunoglobulin E (IgE) in the lung plays a key role in allergic asthmatic inflammation. Asthmatic patients also exhibit elevated serum IgE levels, which may re-equilibrate with the lung IgE pool or enhance IgE-mediated allergic asthma. A seminal finding of IgE downregulation by active IgE immunization was first reported in our lab. This led to the product concept of the mAb omalizumab, and a subsequent collaboration with the pharmaceutical industry led to FDA approval of the Xolair. In the proposed project, the native conformation of receptor-binding IgE loops (e.g., the Xolair binding FG loop epitope) are conformationally constrained in a selected thermostable b-strand pair (dubbed super-b strands) and then fused to an immunogenic and thermostable protein scaffold as a bifunctional vaccine. The use of Imiquimod(IMQ, 3M, Inc.) through a safe transcutaneous route of administration, followed by vaccine IN challenge in saline, ensures that mucosal IgA and IgG subclass anti-IgE antibodies target asthmogenic lung IgE as well as the removal of serum IgE by systemic anti-IgE antibodies. This specific targeting improves safety, and is unlikely to cause type 2 hypersensitivity or chronic urticaria. In the absence of a vaccine reboost, emerging anti-IgE producing B-cells are naturally tolerized by the endogenous self-IgE recovered during the rest period as another safety feature. A ?just-in-time? vaccine reboost is required to break self-IgE tolerance to protect against allergen re-exposure. The lack of persistent IgE suppression preserves IgE competence for parasitic defenses. Our three aims are: Aim 1: Study immunogenicity of human FG supersite vaccine in rodents: location, duration, and efficacies. Aim 2: Evaluate therapeutic vaccination in alleviating IgE-mediated asthmatic inflammation and AHR in rodent models. Aim 3: Evaluate therapeutic vaccination in alleviating IgE-mediated asthmatic inflammation and AHR in rhesus macaques.